ABSTRACT
BACKGROUND/AIM: A hallmark of the progression of prostate cancer to advanced disease is the acquisition of androgen-independent growth. This malignant phenotype is characterized by resistance to conventional treatments and predisposes to formation of hypoxic regions containing stem-like cancer cells. Unfortunately, an effective therapy to target prostate cancer stem cells under hypoxia has not yet been established. In this report, we studied whether δ-tocotrienol (T3), a vitamin E family member that has exhibited the most potent anti-cancer activity, could suppress the survival of prostate cancer stem-like cells. MATERIALS AND METHODS: PC3 stem-like cells were isolated from PC3 parental cells using a three-dimensional culture system. The stemness of the isolated PC3 stem-like cells was confirmed by evaluation of resistance to an anticancer agent (docetaxel) and tumor formation capacity in a xenograft model. The effects of δ-T3 on PC3 stem-like cells under a hypoxia condition were examined by WST-8 (cell viability), real-time reverse transcription-polymerase chain reaction (PCR) and western blotting. RESULTS: δ-T3 demonstrated a cytotoxic effect on prostate cancer stem-like cells in a dose dependent manner and a reduction in the protein levels of hypoxia-inducible factor (HIF)-1α and HIF-2α. Additionally, a specific inhibitor toward HIF-1α induced cytotoxicity on PC3 cells, but selective inhibition of HIF-2α had no effect. CONCLUSION: Overall, these results suggest that δ-T3 could inhibit the survival of prostate cancer stem-like cells under hypoxia, primarily through the inactivation of HIF-1α signaling.
Subject(s)
Adaptation, Physiological/drug effects , Neoplastic Stem Cells/drug effects , Prostatic Neoplasms/drug therapy , Vitamin E/analogs & derivatives , Adaptation, Physiological/genetics , Animals , Cell Hypoxia , Cell Survival/drug effects , Cell Survival/genetics , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hypoxia , Male , Mice, Inbred BALB C , Mice, Nude , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism , Tumor Cells, Cultured , Vitamin E/pharmacology , Vitamins/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
We developed new gossypol (Gos)-based glycoconjugates through dehydration condensation of native Gos and chemically modified glycosides having aminooxy groups. The resultant glycoconjugates (glycoGos) were resistant to hydrolysis, although they were light-sensitive and slowly decomposed even under indoor lighting. The glycoGos also exhibited improved water solubility compared with native Gos, but their saturated concentrations in water were still low (6.4-17⯵M), due to their hydrophobic naphthyl rings. We also carried out WST-8 assays to assess the anticancer activity of the glycoGos on DLD-1 and HepG2 cells and found that the glycoGos having ß-lactosides and having ß-galactosides (specific ligands for asialoglycoprotein receptors) showed enhanced anticancer activity on HepG2 cells.
Subject(s)
Antineoplastic Agents/chemistry , Carbohydrates/chemistry , Gossypol/chemistry , Drug Delivery Systems/methodsABSTRACT
Prostate cancer (PCa) is one of the most common cancers in Western countries and acquires a malignant phenotype, androgen-independent growth. PCa under hypoxia often has resistance to chemotherapy and radiotherapy. However, an effective therapy against PCa under hypoxia has not yet been established. In this report, we investigated the inhibitory effect of a redox-silent analogue of tocotrienol on the survival of a human androgen-independent PCa cell line (PC3) under hypoxia. We found that the redox-silent analogue exerted a cytotoxic effect on PC3 cells in a dose-dependent manner irrespective of either hypoxia or normoxia. Moreover, under hypoxia, the analogue dose dependently reduced the protein levels of hypoxia-inducible factor (HIF)-1α and HIF-2α. In addition, a specific inhibitor toward HIF-1α induced cytotoxicity on PC3 cells, whereas selective inhibition of HIF-2α exerted no effect. Furthermore, suppression of HIFs levels by the analogue in hypoxic PC3 cells was closely associated with the inactivation of Fyn, a member of the nonreceptor tyrosine kinase family, as confirmed by the action of a specific inhibitor toward the kinase (PP2). Taken together, these results suggest that the tocotrienol analogue could inhibit the survival of PC3 cells under hypoxia, mainly by the inhibition of Fyn/HIF-1α signaling, and this may lead to the establishment of a new effective therapy for androgen-independent PCa.
